SUMMARY Although influenza virus has been known for more than a century to be a cause of infectious myocarditis, the underlying mechanisms and susceptibility factors for these cardiac complications are not well understood. Cardiac dysfunction is primarily seen in severe infections, and severe influenza in humans has been reproducibly linked to deleterious polymorphisms in the Interferon-Induced Transmembrane Protein 3 (IFITM3) gene. IFITM3 is an innate immune protein that blocks virus entry into cells and regulates inflammatory immune pathways. Despite the knowledge that IFITM3 influences the outcome of human infections, its role in cardiac complications of influenza has not been previously investigated. Our experiments using a newly developed IFITM3 knockout mouse model indicate that IFITM3 is essential for limiting influenza virus spread to the heart and for preventing cardiac fibrosis and electrical dysfunction caused by the virus. We have also observed that immune cells are depleted from hearts of IFITM3 knockout mice during infection, thus preventing cardiac clearance of virus. In Aim 1, we will investigate the cause of this immune cell depletion by testing the hypothesis that IFITM3-deficient immune cells residing in, or recruited to, the heart are directly infected by virus and undergo apoptosis. In Aim 2, we will identify the mechanism by which fibrosis and cardiac dysfunction occur during infection by testing the hypothesis that virus infection activates specific inflammatory and fibrotic gene profiles in cardiomyocytes and cardiac fibroblasts in the absence of IFITM3. Overall, our research will reveal mechanisms underlying cardiac fibrosis and dysfunction in severe influenza virus infections and will thus identify new strategies for combatting this infection-induced pathology.